rs1936439

Positions:

• chr6-65353620-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001142800.2(EYS):​c.1300-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.678 in 1,606,356 control chromosomes in the GnomAD database, including 370,343 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34623 hom., cov: 31)
  • Exomes 𝑓: 0.68 (335720 hom.)
• Consequence: EYS NM_001142800.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001210
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.199

Genes affected

EYS (HGNC:21555): (eyes shut homolog) The product of this gene contains multiple epidermal growth factor (EGF)-like and LamG domains. The protein is expressed in the photoreceptor layer of the retina, and the gene is mutated in autosomal recessive retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-65353620-G-A is Benign according to our data. Variant chr6-65353620-G-A is described in ClinVar as [Benign]. Clinvar id is 137263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-65353620-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYS	NM_001142800.2	c.1300-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000503581.6
EYS	NM_001142801.2	c.1300-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
EYS	NM_001292009.2	c.1300-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
EYS	NM_198283.2	c.1300-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000503581.6	c.1300-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001142800.2	A2
EYS	ENST00000342421.9	c.1300-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
EYS	ENST00000370621.7	c.1300-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P2
EYS	ENST00000393380.6	c.1300-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.675 AC: 102361 AN: 151758 Hom.: 34610 Cov.: 31

Gnomad AFR AF: 0.690

Gnomad AMI AF: 0.476

Gnomad AMR AF: 0.609

Gnomad ASJ AF: 0.704

Gnomad EAS AF: 0.601

Gnomad SAS AF: 0.712

Gnomad FIN AF: 0.683

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.684

Gnomad OTH AF: 0.647

GnomAD3 exomes AF: 0.671 AC: 168175 AN: 250504 Hom.: 56712 AF XY: 0.675 AC XY: 91353 AN XY: 135386

Gnomad AFR exome AF: 0.684

Gnomad AMR exome AF: 0.622

Gnomad ASJ exome AF: 0.683

Gnomad EAS exome AF: 0.600

Gnomad SAS exome AF: 0.709

Gnomad FIN exome AF: 0.679

Gnomad NFE exome AF: 0.684

Gnomad OTH exome AF: 0.665

GnomAD4 exome AF: 0.678 AC: 986330 AN: 1454480 Hom.: 335720 Cov.: 33 AF XY: 0.680 AC XY: 492000 AN XY: 723924

Gnomad4 AFR exome AF: 0.689

Gnomad4 AMR exome AF: 0.622

Gnomad4 ASJ exome AF: 0.691

Gnomad4 EAS exome AF: 0.585

Gnomad4 SAS exome AF: 0.715

Gnomad4 FIN exome AF: 0.679

Gnomad4 NFE exome AF: 0.681

Gnomad4 OTH exome AF: 0.670

GnomAD4 genome AF: 0.674 AC: 102414 AN: 151876 Hom.: 34623 Cov.: 31 AF XY: 0.672 AC XY: 49883 AN XY: 74210

Gnomad4 AFR AF: 0.690

Gnomad4 AMR AF: 0.609

Gnomad4 ASJ AF: 0.704

Gnomad4 EAS AF: 0.601

Gnomad4 SAS AF: 0.713

Gnomad4 FIN AF: 0.683

Gnomad4 NFE AF: 0.684

Gnomad4 OTH AF: 0.648

Alfa AF: 0.684 Hom.: 17739

Bravo AF: 0.668

Asia WGS AF: 0.643 AC: 2231 AN: 3474

EpiCase AF: 0.685

EpiControl AF: 0.680

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 17, 2023	- -

Retinitis pigmentosa 25 Benign:3

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Retinitis pigmentosa Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.80
DANN	Benign	0.21

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.032
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1936439; hg19: chr6-66063513; COSMIC: COSV60980308;